1. Field of the Invention
This invention relates to a method for the synthesis of sphingosines. More particularly, this invention relates to the synthesis of the four stereoisomers 1-4 of sphingosine by conversion of an achiral starting material.
2. Background of the Invention
Sphingosines constitute a group of related long-chain aliphatic 2-amino-1,3-diols, of which D-erythro-1,3-dihydroxy-2-amino-4,5-trans-octadecene is the most frequently occurring in animal glycosphingolipids. Glycosphingolipids are the glycosides of N-acylsphingosine, the trivial name of which is ceramide. The structural variation in fatty acids, sphingosines, and carbohydrates results in a great number of chemically distinct glycosphingolipids. Thus, sphingosines and their derivatives, glycosphingolipids, are of interest because of their diverse bioactivities and biological roles. These activities include inhibition of protein kinase C activity and transfer of information between developing vertebrate cells. Sphingosines also serve as chain terminators in various gangliosides. Galactosyl ceramide has been shown to be a receptor for HIV binding in cells lacking the CD4 receptor.
In order to obtain valuable sphingosine derivatives, it is useful to first synthesize optically pure sphingosine in all its isomeric forms: ##STR1##
Previous methods of synthesizing optically pure sphingosines have relied on the use of serine as a chiral building block. For example, Newman, J. Am. Chem., 95(12):4098 (1973); Boutin et al., J. Org. Chem., 51:5320 (1986); Garner et al, J. Org. Chem., 53:4395 (1988); Polt et al., J. Org. Chem., 57:5469 (1992); Herold, Helv. Chim. Acta, 71:354 (1988); Nimkar et al., Tetrahedron Letter, 29(25):3037 (1988); and U.S. Pat. No. 5,110,987, describe the preparation of sphingosine or its derivatives from serine or related compounds. These methods are disadvantageous due to the impossibility of obtaining all four stereoisomers of sphingosine from the same starting compound. Moreover, methods utilizing serine as a starting material are quite lengthy and, thus, are not amenable to potential scale-up.
Another effort to synthesize optically pure sphingosines utilized the stereospecific hydration of chlorofumaric acid with fumarase to give L-threo-chloromalic acid as a chiral pool reagent and result in the synthesis of D-erythrosphingosine, as described in Findeis et al., J. Org. Chem., 52:2838-2848 (1987). This method is complicated and only results in the synthesis of one stereoisomer of sphingosine.
Several attempts to obtain optically pure sphingosines have utilized carbohydrates as starting materials. In Zimmermann and Schmidt et al., Liebigs Ann. Chem., 663 (1988), a method of synthesizing D-erythro-sphingosine is described utilizing D-galactose. U.S. Pat. No. 4,937,328 describes the synthesis of sphingosine derivatives from D-galactose. Obayashi et al., Chemistry Letters, pp. 1715-1718 (1985), describes synthesis of sphingosines using sugar precursors. Using sugars as the starting material locks the design into a particular configuration of stereocenters. The necessary manipulations and inversions required to get a desired isomer then lengthen the synthesis process.
Despite the prior efforts, an efficient method for the synthesis of sphingosines has not heretofore been available. Further, there is a need in the art for a method for synthesizing sphingosines which enables the production of a desired stereoisomer.
Therefore, it is an object of the present invention to provide a general method for the synthesis of all sphingosines.
It is further an object of the present invention to provide a method for the synthesis of the four stereoisomers of sphingosine from the same starting material.
It is further an object of the present invention to provide a method for the synthesis of sphingosine using an easily obtainable starting material.
It is further an object of the present invention to provide a method for the synthesis of sphingosine which can yield the product in a minimum number of steps.
It is further an object of the present invention to provide an environmentally acceptable method for the synthesis of sphingosine.
These and other objects of the present invention will become apparent upon review of the following specification and the claims appended thereto.